Implication of Preoperative Existence of Atrial Fibrillation on Hemocompatibility-Related Adverse Events During Left Ventricular Assist Device Support.
Hemocompatibility-related adverse events (HRAEs) are substantial issues in patients with left ventricular assist devices (LVADs). Atrial fibrillation (AF) is associated with worse prognosis in patients with heart failure (HF), but its effect on HRAEs following LVAD implantation remain uncertain.Methods and Results:Data from the Japanese Mechanically Assisted Circulatory Support registry of consecutive patients who received HeartMate II LVADs and were followed for 1 year were retrospectively reviewed. Among 190 patients, 23 had AF and 167 had sinus rhythm. The AF group had comparable baseline characteristics with the non-AF group except for their higher age (53 vs. 42 years, P<0.001). Following LVAD implantation, most cases of AF (73%) persisted. Antiplatelet therapy, anticoagulation therapy, and LVAD speed following LVAD implantation were comparable between groups (P>0.05 for all). The 1-year survival free from HRAEs was comparable between groups (83% vs. 76%, P=0.52). Event rates of the breakdown of HRAEs were comparable between groups except for a relatively higher rate of surgically managed pump thrombosis in the AF group (0.16 vs. 0.04, incidence rate ratio 3.75, 95% confidence interval 0.87-16.1, P=0.075). These trends still remained with propensity score-matched comparison. Existence of AF had no effect on the development of HRAEs following LVAD implantation. The need to aggressively treat AF before or after LVAD implantation needs further investigation.


Therapeutic Basis of Clinical Pain Modulation.
Pain is a hallmark of almost all bodily ailments and can be modulated by agents, including analgesics and anesthetics that suppress pain signals in the central nervous system. Defects in the modulatory systems, including the endogenous pain-inhibitory pathways, are a major factor in the initiation and chronicity of pain. Thus, pain modulation is particularly applicable to the practice of medicine. This review summarizes the existing literature on pain modulation. Here, we critically reviewed the literature from PubMed on pain modulation published primarily within the past 5 years in high impact journals. Specifically, we have discussed important anatomical landmarks of pain modulation and outlined the endogenous networks and underlying mechanisms of clinically relevant pain modulatory methods. The Gate Control Theory is briefly presented with discussion on the capacity of pain modulation to cause both hyper- and hypoalgesia. An emphasis has been given to highlight key areas in pain research that, because of unanswered questions or therapeutic potential, merit additional scientific scrutiny. The information presented in this paper would be helpful in developing novel therapies, metrics, and interventions for improved patient management.


An ATP-binding membrane protein is required for protein translocation across the endoplasmic reticulum membrane.
The role of nucleotides in providing energy for polypeptide transfer across the endoplasmic reticulum (ER) membrane is still unknown. To address this question, we treated ER-derived mammalian microsomal vesicles with a photoactivatable analogue of ATP, 8-N3ATP. This treatment resulted in a progressive inhibition of translocation activity. Approximately 20 microsomal membrane proteins were labeled by [alpha 32P]8-N3ATP. Two of these were identified as proteins with putative roles in translocation, alpha signal sequence receptor (SSR), the 35-kDa subunit of the signal sequence receptor complex, and ER-p180, a putative ribosome receptor. We found that there was a positive correlation between inactivation of translocation activity and photolabeling of alpha SSR. In contrast, our data demonstrate that the ATP-binding domain of ER-p180 is dispensable for translocation activity and does not contribute to the observed 8-N3ATP sensitivity of the microsomal vesicles.


A nationwide database linking information on the hosts with sequence data of their virus strains: A useful tool for the eradication of bovine viral diarrhea (BVD) in Switzerland.
Pestiviruses infect a wide variety of animals of the order Artiodactyla, with bovine viral diarrhea virus (BVDV) being an economically important pathogen of livestock globally. BVDV is maintained in the cattle population by infecting fetuses early in gestation and, thus, by generating persistently infected (PI) animals that efficiently transmit the virus throughout their lifetime. In 2008, Switzerland started a national control campaign with the aim to eradicate BVDV from all bovines in the country by searching for and eliminating every PI cattle. Different from previous eradication programs, all animals of the entire population were tested for virus within one year, followed by testing each newborn calf in the subsequent four years. Overall, 3,855,814 animals were tested from 2008 through 2011, 20,553 of which returned an initial BVDV-positive result. We were able to obtain samples from at least 36% of all initially positive tested animals. We sequenced the 5' untranslated region (UTR) of more than 7400 pestiviral strains and compiled the sequence data in a database together with an array of information on the PI animals, among others, the location of the farm in which they were born, their dams, and the locations where the animals had lived. To our knowledge, this is the largest database combining viral sequences with animal data of an endemic viral disease. Using unique identification tags, the different datasets within the database were connected to run diverse molecular epidemiological analyses. The large sets of animal and sequence data made it possible to run analyses in both directions, i.e., starting from a likely epidemiological link, or starting from related sequences. We present the results of three epidemiological investigations in detail and a compilation of 122 individual investigations that show the usefulness of such a database in a country-wide BVD eradication program.


Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas.
Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs. To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine. All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up. This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.


Approximating evolutionary dynamics on networks using a Neighbourhood Configuration model.
Evolutionary dynamics have been traditionally studied on homogeneously mixed and infinitely large populations. However, real populations are finite and characterised by complex interactions among individuals. Recent studies have shown that the outcome of the evolutionary process might be significantly affected by the population structure. Although an analytic investigation of the process is possible when the contact structure of the population has a simple form, this is usually infeasible on complex structures and the use of various assumptions and approximations is necessary. In this paper, we adopt an approximation method which has been recently used for the modelling of infectious disease transmission to model evolutionary game dynamics on complex networks. Comparisons of the predictions of the model constructed with the results of computer simulations reveal the effectiveness of the method and the improved accuracy that it provides when, for example, compared to well-known pair approximation methods. This modelling framework offers a flexible way to carry out a systematic analysis of evolutionary game dynamics on graphs and to establish the link between network topology and potential system behaviours. As an example, we investigate how the Hawk and Dove strategies in a Hawk-Dove game spread in a population represented by a random regular graph, a random graph and a scale-free network, and we examine the features of the graph which affect the evolution of the population in this particular game.


Factors associated with antiretroviral treatment uptake and adherence: a review. Perspectives from Australia, Canada, and the United Kingdom.
International focus on reducing onward HIV transmission emphasizes the need for routine HIV testing and early uptake of antiretroviral treatment (ART). Strategic targets have been set for 2020 to achieve the goal of 90% of people infected with HIV diagnosed, 90% of identified cases on treatment, and 90% of persons on treatment virally suppressed (90-90-90). It is vital to understand the complexity of factors influencing a person's treatment decisions over time and the context which may enable better adherence. In this paper we present findings from the review of published and gray literature (2003-2013) on the documented factors associated with treatment initiation and adherence in the general adult population of Australia, Canada, and the UK. A framework developed by Begley, McLaws, Ross, and Gold [2008. Cognitive and behavioural correlates of non-adherence to HIV anti-retroviral therapy: Theoretical and practical insight for clinical psychology and health psychology. Clinical Psychologist, 12(1), 9-17] in Australia was adapted to summarize the findings. A systematic database search using keywords and a set of inclusion criteria yielded 17 studies (Australia = 6; Canada = 8; UK = 3). In addition 11 reports were included in the review. We found that a person's abilities and motivations (intrapersonal factors, reported in 7 studies) to start and continue ART are influenced by a host of interconnected factors spanning relationship (interpersonal, 3 studies) and broader structural (extrapersonal, 15 studies) factors that are situated within social determinants of health. People therefore evaluate various costs and benefits of starting and staying on treatment, in which biomedical concerns play an important yet often subsidiary role. In this review the economic barriers to care were found to be significant and under-reported, highlighting the persistent health inequities in terms of access to services. Our understanding of the context around people's use of ART remains poor. Qualitative social research within HIV-positive communities is urgently needed to capture people's lived experiences and may address some of this deficit in understanding.


Psychological Strategies Included by Strength and Conditioning Coaches in Applied Strength and Conditioning.
This study provided the basis by which professional development needs can be addressed and add to the applied sport psychology literature from an underresearched sport domain. This study endeavored to use qualitative methods to explore the specific techniques applied by the strength and conditioning professional. Eighteen participants were recruited for interview, through convenience sampling, drawn from a previously obtained sample. Included in the study were 10 participants working within the United Kingdom, 3 within the United States, and 5 within Australia offering a cross section of experience from ranging sport disciplines and educational backgrounds. Participants were interviewed using semistructured interviews. Thematic clustering was used by interpretative phonological analysis to identify common themes. The practitioners referred to a wealth of psychological skills and strategies that are used within strength and conditioning. Through thematic clustering, it was evident that a significant emphasis is on the development or maintenance of athlete self-confidence specifically with a large focus on goal setting. Similarly, albeit to a lesser extent, there was a notable attention on skill acquisition and arousal management strategies. The strategies used by the practitioners consisted of a combination of cognitive strategies and behavioral strategies. It is important to highlight the main psychological strategies that are suggested by strength and conditioning coaches themselves to guide professional development toward specific areas. Such development should strive to develop coaches' awareness of strategies to develop confidence, regulate arousal, and facilitate skill and technique development.


Microleakage of resin composite restorations with glass-ceramic inserts.
The purpose of this study was to evaluate the effects of glass-ceramic inserts and different application techniques of resin composites on marginal leakage. Three groups of 10 standardized, round, Class V cavities were prepared on the buccal surface of 30 extracted human molar teeth. Group 1 received resin composite restorations, placed in one increment (bulk). Group 2 received resin composite restorations that were placed in two increments, and group 3 received resin composite restorations with beta-quartz ceramic inserts. After the teeth were thermocycled and placed in 0.5% basic fuchsin for 24 hours, they were sectioned and examined for microleakage. On the occlusal margins, there was no statistically significant difference between the restorations placed with the incremental technique and the restorations with beta-quartz inserts. The restorations placed with the bulk technique had significantly more microleakage than did the others. On the gingival margins, the restorations with beta-quartz inserts exhibited significantly less microleakage than did the other groups. The restorations placed with the bulk technique showed significantly more dye penetration than did the others. The use of a glass-ceramic insert reduced the marginal leakage of Class V resin composite restorations.


A Paradigm for CH Bond Cleavage: Structural and Functional Aspects of Transition State Stabilization by Mandelate Racemase.
Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg2+-dependent, 1,1-proton transfer reaction that racemizes (R)- and (S)-mandelate. MR shares a partial reaction (i.e., the metal ion-assisted, Brønsted base-catalyzed proton abstraction of the α-proton of carboxylic acid substrates) and structural features ((β/α)7β-barrel and N-terminal α + β capping domains) with a vast group of homologous, yet functionally diverse, enzymes in the enolase superfamily. Mechanistic and structural studies have developed this enzyme into a paradigm for understanding how enzymes such as those of the enolase superfamily overcome kinetic and thermodynamic barriers to catalyze the abstraction of an α-proton from a carbon acid substrate with a relatively high pKa value. Structural studies on MR bound to intermediate/transition state analogues have delineated those structural features that MR uses to stabilize transition states and enhance reaction rates of proton abstraction. Kinetic, site-directed mutagenesis, and structural studies have also revealed that the phenyl ring of the substrate migrates through the hydrophobic cavity within the active site during catalysis and that the Brønsted acid-base catalysts (Lys 166 and His 297) may be utilized as binding determinants for inhibitor recognition. In addition, structural studies on the adduct formed from the irreversible inhibition of MR by 3-hydroxypyruvate revealed that MR can form and deprotonate a Schiff-base with 3-hydroxypyruvate to yield an enol(ate)-aldehyde adduct, suggesting a possible evolutionary link between MR and the Schiff-base forming aldolases. As the archetype of the enolase superfamily, mechanistic and structural studies on MR will continue to enhance our understanding of enzyme catalysis and furnish insights into the evolution of enzyme function.


Foraging rate versus sociality in the starling Sturnus vulgaris.
It is well established that social conditions often modify foraging behaviour, but the theoretical interpretation of the changes produced is not straightforward. Changes may be due to alterations of the foraging currency (the mathematical expression that behaviour maximizes) and/or of the available resources. An example of the latter is when both solitary and social foragers maximize rates of gain over time, but competition alters the behaviour required to achieve this, as assumed by ideal free distribution models. Here we examine this problem using captive starlings Sturnus vulgaris. Subjects had access to two depleting patches that replenished whenever the alternative patch was visited. The theoretical rate-maximizing policy was the same across all treatments, and consisted of alternating between patches following a pattern that could be predicted using the marginal value theorem (MVT). There were three treatments that differed in the contents of an aviary adjacent to one of the two patches (called the 'social' patch). In the control treatment, the aviary was empty, in the social condition it contained a group of starlings, and in a non-specific stimulus control it contained a group of zebra finches. In the control condition both patches were used equally and behaviour was well predicted by the MVT. In the social condition, starlings foraged more slowly in the social than in the solitary patch. Further, foraging in the solitary patch was faster and in the social patch slower in the social condition than in the control condition. Although these changes are incompatible with overall rate maximization (gain rate decreased by about 24% by self-imposed changes), if the self-generated gain functions were used the MVT was a good predictor of patch exploitation under all conditions. We discuss the complexities of nesting optimal foraging models in more comprehensive theoretical accounts of behaviour integrating functional and mechanistic perspectives.


Immunogenicity, protective efficacy and mechanism of novel CCS adjuvanted influenza vaccine.
We optimized the immunogenicity of adjuvanted seasonal influenza vaccine based on commercial split influenza virus as an antigen (hemagglutinin = HA) and on a novel polycationic liposome as a potent adjuvant and efficient antigen carrier (CCS/C-HA vaccine). The vaccine was characterized physicochemically, and the mechanism of action of CCS/C as antigen carrier and adjuvant was studied. The optimized CCS/C-HA split virus vaccine, when administered intramuscularly (i.m.), is significantly more immunogenic in mice, rats and ferrets than split virus HA vaccine alone, and it provides for protective immunity in ferrets and mice against live virus challenge that exceeds the degree of efficacy of the split virus vaccine. Similar adjuvant effects of optimized CCS/C are also observed in mice for H1N1 swine influenza antigen. The CCS/C-HA vaccine enhances immune responses via the Th1 and Th2 pathways, and it increases both the humoral responses and the production of IL-2 and IFN-γ but not of the pro-inflammatory factor TNFα. In mice, levels of CD4(+) and CD8(+) T-cells and of MHC II and CD40 co-stimulatory molecules are also elevated. Structure-function relationship studies of the CCS molecule as an adjuvant/carrier show that replacing the saturated palmitoyl acyl chain with the mono-unsaturated oleoyl (C18:1) chain affects neither size distribution and zeta potential nor immune responses in mice. However, replacing the polyalkylamine head group spermine (having two secondary amines) with spermidine (having only one secondary amine) reduces the enhancement of the immune response by ∼ 50%, while polyalkylamines by themselves are ineffective in improving the immunogenicity over the commercial HA vaccine. This highlights the importance of the particulate nature of the carrier and the polyalkylamine secondary amines in the enhancement of the immune responses against seasonal influenza. Altogether, our results suggest that the CCS/C polycationic liposomes combine the activities of a potent adjuvant and efficient carrier of seasonal and swine flu vaccines and support further development of the CCS/C-HA vaccine.


New artificial intelligence prediction model using serial prothrombin time international normalized ratio measurements in atrial fibrillation patients on vitamin K antagonists: GARFIELD-AF.
Most clinical risk stratification models are based on measurement at a single time-point rather than serial measurements. Artificial intelligence (AI) is able to predict one-dimensional outcomes from multi-dimensional datasets. Using data from Global Anticoagulant Registry in the Field (GARFIELD)-AF registry, a new AI model was developed for predicting clinical outcomes in atrial fibrillation (AF) patients up to 1 year based on sequential measures of prothrombin time international normalized ratio (PT-INR) within 30 days of enrolment. Patients with newly diagnosed AF who were treated with vitamin K antagonists (VKAs) and had at least three measurements of PT-INR taken over the first 30 days after prescription were analysed. The AI model was constructed with multilayer neural network including long short-term memory and one-dimensional convolution layers. The neural network was trained using PT-INR measurements within days 0-30 after starting treatment and clinical outcomes over days 31-365 in a derivation cohort (cohorts 1-3; n = 3185). Accuracy of the AI model at predicting major bleed, stroke/systemic embolism (SE), and death was assessed in a validation cohort (cohorts 4-5; n = 1523). The model's c-statistic for predicting major bleed, stroke/SE, and all-cause death was 0.75, 0.70, and 0.61, respectively. Using serial PT-INR values collected within 1 month after starting VKA, the new AI model performed better than time in therapeutic range at predicting clinical outcomes occurring up to 12 months thereafter. Serial PT-INR values contain important information that can be analysed by computer to help predict adverse clinical outcomes.


Effect of a 24-Month Physical Activity Intervention vs Health Education on Cognitive Outcomes in Sedentary Older Adults: The LIFE Randomized Trial.
Epidemiological evidence suggests that physical activity benefits cognition, but results from randomized trials are limited and mixed. To determine whether a 24-month physical activity program results in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program. A randomized clinical trial, the Lifestyle Interventions and Independence for Elders (LIFE) study, enrolled 1635 community-living participants at 8 US centers from February 2010 until December 2011. Participants were sedentary adults aged 70 to 89 years who were at risk for mobility disability but able to walk 400 m. A structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching. Prespecified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding (DSC) task subtest of the Wechsler Adult Intelligence Scale (score range: 0-133; higher scores indicate better function) and the revised Hopkins Verbal Learning Test (HVLT-R; 12-item word list recall task) assessed in 1476 participants (90.3%). Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months. At 24 months, DSC task and HVLT-R scores (adjusted for clinic site, sex, and baseline values) were not different between groups. The mean DSC task scores were 46.26 points for the physical activity group vs 46.28 for the health education group (mean difference, -0.01 points [95% CI, -0.80 to 0.77 points], P = .97). The mean HVLT-R delayed recall scores were 7.22 for the physical activity group vs 7.25 for the health education group (mean difference, -0.03 words [95% CI, -0.29 to 0.24 words], P = .84). No differences for any other cognitive or composite measures were observed. Participants in the physical activity group who were 80 years or older (n = 307) and those with poorer baseline physical performance (n = 328) had better changes in executive function composite scores compared with the health education group (P = .01 for interaction for both comparisons). Incident MCI or dementia occurred in 98 participants (13.2%) in the physical activity group and 91 participants (12.1%) in the health education group (odds ratio, 1.08 [95% CI, 0.80 to 1.46]). Among sedentary older adults, a 24-month moderate-intensity physical activity program compared with a health education program did not result in improvements in global or domain-specific cognitive function. clinicaltrials.gov Identifier: NCT01072500.


Navigation and analysis of the energy landscape of small proteins using the activation-relaxation technique.
The resolution of the protein folding problem has been tied to the development of a detailed understanding of the configurational energy or of the free energy landscape associated with these molecules. Using the activation-relaxation technique and a simplified energy model, we present here a detailed analysis of the energy landscape of 16-residue peptide that folds into a beta-hairpin. Our results support the concept of an energy landscape with an effective topology consistent with a scale-free network.


MUC1 expressed in PanC1 cells decreases adhesion to type 1 collagen but increases contraction in collagen lattices.
A subline of human pancreatic cells (PanC1) that expresses low levels of cytokeratins 8 and 18 but not MUC1 mucin was transfected with both 3.5-kb and 3.9-kb full-length MUC1 cDNA. The MUC1-positive clone expressing the larger mucin was shown to express increased levels of cytokeratins 8 and 18 compared with the parental line or vector controls. Growth of these MUC1-transfected cells in type I collagen gels produced marked gel contraction that could be significantly reduced by the synthetic peptide SRGDTG or by growth in serum and fibronectin-depleted media. Cellular binding to type I collagen was found to be reduced by two- to four-fold in cells expressing the MUC1 mucin, for which the greatest inhibition was observed in cells expressing the larger form. No difference in cellular binding to fibronectin was observed. From these data we conclude that the human MUC1 mucin modifies the differentiated state of human pancreatic cells by altering cytokeratin expression and reducing adhesion to type I collagen but paradoxically enhancing the cellular contractile phenotype, effects that appear to be mediated by integrin expression and/or function.


Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort.
Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 μg/L and 4.3 mg/L in cases and 85.6 μg/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR = 0.92, 95% CI: 0.82-1.03 per 25 μg/L increase). However, sub-group analyses by sex showed a statistically significant association for women (p(trend) = 0.032; per 25 μg/L Se increase, IRR = 0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (p(trend) = 0.009; per 0.806 mg/L increase, IRR = 0.89, 95% CI: 0.82-0.98) with the association more apparent in women (p(trend) = 0.004; IRR = 0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (p(trend) = 0.485; IRR = 0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.


Predicting chemical shifts with graph neural networks.
Inferring molecular structure from Nuclear Magnetic Resonance (NMR) measurements requires an accurate forward model that can predict chemical shifts from 3D structure. Current forward models are limited to specific molecules like proteins and state-of-the-art models are not differentiable. Thus they cannot be used with gradient methods like biased molecular dynamics. Here we use graph neural networks (GNNs) for NMR chemical shift prediction. Our GNN can model chemical shifts accurately and capture important phenomena like hydrogen bonding induced downfield shift between multiple proteins, secondary structure effects, and predict shifts of organic molecules. Previous empirical NMR models of protein NMR have relied on careful feature engineering with domain expertise. These GNNs are trained from data alone with no feature engineering yet are as accurate and can work on arbitrary molecular structures. The models are also efficient, able to compute one million chemical shifts in about 5 seconds. This work enables a new category of NMR models that have multiple interacting types of macromolecules.


Homoleptic nickel(II) complexes of redox-tunable pincer-type ligands.
Different synthetic methods have been developed to prepare eight new redox-active pincer-type ligands, H(X,Y), that have pyrazol-1-yl flanking donors attached to an ortho-position of each ring of a diarylamine anchor and that have different groups, X and Y, at the para-aryl positions. Together with four previously known H(X,Y) ligands, a series of 12 Ni(X,Y)2 complexes were prepared in high yields by a simple one-pot reaction. Six of the 12 derivatives were characterized by single-crystal X-ray diffraction, which showed tetragonally distorted hexacoordinate nickel(II) centers. The nickel(II) complexes exhibit two quasi-reversible one-electron oxidation waves in their cyclic voltammograms, with half-wave potentials that varied over a remarkable 700 mV range with the average of the Hammett σ(p) parameters of the para-aryl X, Y groups. The one- and two-electron oxidized derivatives [Ni(Me,Me)2](BF4)n (n = 1, 2) were prepared synthetically, were characterized by X-band EPR, electronic spectroscopy, and single-crystal X-ray diffraction (for n = 2), and were studied computationally by DFT methods. The dioxidized complex, [Ni(Me,Me)2](BF4)2, is an S = 2 species, with nickel(II) bound to two ligand radicals. The mono-oxidized complex [Ni(Me,Me)2](BF4), prepared by comproportionation, is best described as nickel(II) with one ligand centered radical. Neither the mono- nor the dioxidized derivative shows any substantial electronic coupling between the metal and their bound ligand radicals because of the orthogonal nature of their magnetic orbitals. On the other hand, weak electronic communication occurs between ligands in the mono-oxidized complex as evident from the intervalence charge transfer (IVCT) transition found in the near-IR absorption spectrum. Band shape analysis of the IVCT transition allowed comparisons of the strength of the electronic interaction with that in the related, previously known, Robin-Day class II mixed valence complex, [Ga(Me,Me)2](2+).


Chromosome 9p21 in sporadic amyotrophic lateral sclerosis in the UK and seven other countries: a genome-wide association study.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons that results in progressive weakness and death from respiratory failure, commonly within about 3 years. Previous studies have shown association of a locus on chromosome 9p with ALS and linkage with ALS-frontotemporal dementia. We aimed to test whether this genomic region is also associated with ALS in an independent set of UK samples, and to identify risk factors associated with ALS in a further genome-wide association study that combined data from the independent analysis with those from other countries. We collected samples from patients with sporadic ALS from 20 UK hospitals and obtained UK control samples from the control groups of the Depression Case Control study, the Bipolar Affective Case Control Study, and the British 1958 birth cohort DNA collection. Genotyping of DNA in this independent analysis was done with Illumina HumanHap550 BeadChips. We then undertook a joint genome-wide analysis that combined data from the independent set with published data from the UK, USA, Netherlands, Ireland, Italy, France, Sweden, and Belgium. The threshold for significance was p=0·05 in the independent analysis, because we were interested in replicating a small number of previously reported associations, whereas the Bonferroni-corrected threshold for significance in the joint analysis was p=2·20×10(-7) After quality control, samples were available from 599 patients and 4144 control individuals in the independent set. In this analysis, two single nucleotide polymorphisms in a locus on chromosome 9p21.2 were associated with ALS: rs3849942 (p=2·22×10(-6); odds ratio [OR] 1·39, 95% CI 1·21-1·59) and rs2814707 (p=3·32×10(-6); 1·38, 1·20-1·58). In the joint analysis, which included samples from 4312 patients with ALS and 8425 control individuals, rs3849942 (p=4·64×10(-10); OR 1·22, 95% CI 1·15-1·30) and rs2814707 (p=4·72×10(-10); 1·22, 1·15-1·30) were associated with ALS. We have found strong evidence of a genetic association of two single nucleotide polymorphisms on chromosome 9 with sporadic ALS, in line with findings from previous independent GWAS of ALS and linkage studies of ALS-frontotemporal dementia. Our findings together with these earlier findings suggest that genetic variation at this locus on chromosome 9 causes sporadic ALS and familial ALS-frontotemporal dementia. Resequencing studies and then functional analysis should be done to identify the defective gene.


Necessary conditions for the perception of motion in depth.
This study investigated the relation between the perception of motion in depth and ocular vergence movements for a single foveally viewed dot, and for a 30 deg X 30 deg pattern of many dots. When the target's disparity was changed, it appeared to move in depth relative to stationary reference marks, but removing the reference marks completely abolished the sensation of motion in depth for the multi-dot target and left only a weak sensation of motion in depth for the single dot target. However, it is not the case that motion-in-depth sensation per se depends on the presence of reference marks; motion in depth generated by changing-size stimulation was unaffected by removing reference marks. Possible explanations for the loss of motion-in-depth sensation include ocular vergence exactly tracked stimulus motion; vergence changes and disparity changes, though unequal, produced equal and opposite motion-in-depth signals; vergence changes, though producing no motion-in-depth signals, suppressed the signals produced by disparity changes; motion-in-depth sensation requires relative motion. Explanation is rejected because vergence tracking errors were large. Explanation is rejected because vergence changes do not in themselves induce a sensation of motion in depth. Explanation is rejected because motion-in-depth threshold is not affected by vergence changes. Conclusions are as follows. For a single-dot target, visual sensitivity to motion in depth is much higher for changes in relative retinal disparity than for changes in absolute retinal disparity, while for a multi-dot target any residual sensitivity is abolished by an interaction between neighboring coherently moving dots. The authors suggest that the relative velocity elements proposed to explain sensitivity to changing size feed the stereomotion mechanism also.


[A national birth weight distribution curve according to gestational age in Chile from 1993 to 2000].
The World Health Organization recently defined the criteria for constructing birth weight curves using population based data. To construct a national curve of weight, size and ponderal index at birth for Chile, following the criteria suggested by the World Health Organization (WHO) expert committee report from 1995. A national database from the Chilean Istitute for Statistics was used. All alive singleton deliveries during tbe period from 1993 to 2000 were included. A birth weight curve for the total population as well as for size and ponderal index at birth was construted, including percentile distribution, mean and standard deviation of values for gestational age. Stratification by sex was performed. A total of 2,049,446 singleton deliveries were analyzed. The 10 percentiles (raw data) for birth weight throughout gestation from 22 to 42 weeks were: 470, 520, 560, 630, 660, 749, 810, 926, 1,031, 1,160, 1,320, 1,480, 1,680, 1,920, 2,190, 2,500, 2, 750, 2,910, 3,010, 3,080 and 3,090 g, respectively. A national birth weight for Chilean population (a predominant Hispanic population) was constructed. There are not differences between this curve and the standard proposed by WHO (population from California, USA) suggesting that under comparable perinatal indices, ethnicity is not a relevant factor deterimining birth weight.


Dietary fibre in food and protection against colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC): an observational study.
Dietary fibre is thought to protect against colorectal cancer but this view has been challenged by recent prospective and intervention studies that showed no protective effect. We prospectively examined the association between dietary fibre intake and incidence of colorectal cancer in 519978 individuals aged 25-70 years taking part in the EPIC study, recruited from ten European countries. Participants completed a dietary questionnaire in 1992-98 and were followed up for cancer incidence. Relative risk estimates were obtained from fibre intake, categorised by sex-specific, cohort-wide quintiles, and from linear models relating the hazard ratio to fibre intake expressed as a continuous variable. Follow-up consisted of 1939011 person-years, and data for 1065 reported cases of colorectal cancer were included in the analysis. Dietary fibre in foods was inversely related to incidence of large bowel cancer (adjusted relative risk 0.75 [95% CI 0.59-0.95] for the highest versus lowest quintile of intake), the protective effect being greatest for the left side of the colon, and least for the rectum. After calibration with more detailed dietary data, the adjusted relative risk for the highest versus lowest quintile of fibre from food intake was 0.58 (0.41-0.85). No food source of fibre was significantly more protective than others, and non-food supplement sources of fibre were not investigated. In populations with low average intake of dietary fibre, an approximate doubling of total fibre intake from foods could reduce the risk of colorectal cancer by 40%.


Competing interests, clashing ideas and institutionalizing influence: insights into the political economy of malaria control from seven African countries.
This article explores how malaria control in sub-Saharan Africa is shaped in important ways by political and economic considerations within the contexts of aid-recipient nations and the global health community. Malaria control is often assumed to be a technically driven exercise: the remit of public health experts and epidemiologists who utilize available data to select the most effective package of activities given available resources. Yet research conducted with national and international stakeholders shows how the realities of malaria control decision-making are often more nuanced. Hegemonic ideas and interests of global actors, as well as the national and global institutional arrangements through which malaria control is funded and implemented, can all influence how national actors respond to malaria. Results from qualitative interviews in seven malaria-endemic countries indicate that malaria decision-making is constrained or directed by multiple competing objectives, including a need to balance overarching global goals with local realities, as well as a need for National Malaria Control Programmes to manage and coordinate a range of non-state stakeholders who may divide up regions and tasks within countries. Finally, beyond the influence that political and economic concerns have over programmatic decisions and action, our analysis further finds that malaria control efforts have institutionalized systems, structures and processes that may have implications for local capacity development.


Nitric oxide in serum and renal tissue during compensatory renal hypertrophy in rats.
Nitric oxide (NO) level in serum and renal tissue has been examined in 15 male Wistar rats, body weight 200-250 g, 7 days after unilateral nephrectomy. All rats were ether-anaesthetized and the kidneys were removed by dorsolateral approach. NO concentration in serum and renal tissue was determined by classic colorimetric Griess reaction. Conversion of NO(3)(2-) into NO(2)(2-) was done with elementary zinc. Results have shown that NO concentration in renal tissue is statistically higher in rats 7 days after unilateral nephrectomy then in control renal tissue before compensatory kidney growth (p<0,02). There is no difference between NO concentration in serum before unilateral nephrectomy and 7 days after nephrectomy. These findings suggest that NO may play an important role in mediating the hemodynamic changes associated with reduced renal mass.


Correlated 5-Hydroxymethylcytosine (5hmC) and Gene Expression Profiles Underpin Gene and Organ-Specific Epigenetic Regulation in Adult Mouse Brain and Liver.
DNA methylation is an epigenetic mechanism essential for gene regulation and vital for mammalian development. 5-hydroxymethylcytosine (5hmC) is the first oxidative product of the TET-mediated 5-methylcytosine (5mC) demethylation pathway. Aside from being a key intermediate in cytosine demethylation, 5hmC may have potential regulatory functions with emerging importance in mammalian biology. Here, we investigate the global 5hmC enrichment in five brain structures, including cerebellum, cerebral cortex, hippocampus, hypothalamus and thalamus, as well as liver tissues from female and male adult mice by using chemical capture-based technique coupled with next-generation sequencing. At the same time, we carried out total RNA sequencing (RNA-seq) to analyze the transcriptomes of brain regions and liver tissues. Our results reveal preferential 5hmC enrichment in the gene bodies of expressed genes, and 5hmC levels of many protein-coding genes are positively correlated with RNA expression intensity. However, more than 75% of genes with low or no 5hmC enrichment are genes encode for mitochondrial proteins and ribosomal proteins despite being actively transcribed, implying different transcriptional regulation mechanisms of these housekeeping genes. Brain regions developed from the same embryonic structures have more similar 5hmC profiles. Also, the genic 5hmC enrichment pattern is highly tissue-specific, and 5hmC marks genes involving in tissue-specific biological processes. Sex chromosomes are mostly depleted of 5hmC, and the X inactive specific transcript (Xist) gene located on the X chromosome is the only gene to show sex-specific 5hmC enrichment. This is the first report of the whole-genome 5hmC methylome of five major brain structures and liver tissues in mice of both sexes. This study offers a comprehensive resource for future work of mammalian cytosine methylation dynamics. Our findings offer additional evidence that suggests 5hmC is an active epigenetic mark stably maintained after the global reprogramming event during early embryonic development.


Circuitry underlying antiopioid actions of cholecystokinin within the rostral ventromedial medulla.
It is now well established that the analgesic actions of opioids can be modified by "anti-analgesic" or "antiopioid" peptides, among them cholecystokinin (CCK). Although the focus of much recent work concerned with CCK-opioid interactions has been at the level of the spinal cord, CCK also acts within the brain to modify opioid analgesia. The aim of the present study was to characterize the actions of CCK in a brain region in which the circuitry mediating the analgesic actions of opioids is relatively well understood, the rostral ventromedial medulla (RVM). Single-cell recording was combined with local infusion of CCK in the RVM and systemic administration of morphine in lightly anesthetized rats. The tail-flick reflex was used as a behavioral index of nociceptive responsiveness. Two classes of RVM neurons with distinct responses to opioids have been identified. OFF cells are activated, indirectly, by morphine and mu-opioid agonists, and there is strong evidence that this activation is crucial to opioid antinociception. ON cells, thought to facilitate nociception, are directly inhibited by opioids. Cells of a third class, NEUTRAL cells, do not respond to opioids, and whether they have any role in nociceptive modulation is unknown. CCK microinjected into the RVM by itself had no effect on tail flick latency or the firing of any cell class but significantly attenuated opioid activation of OFF cells and inhibition of the tail flick. Opioid suppression of ON-cell firing was not significantly altered by CCK. Thus CCK acting within the RVM attenuates the analgesic effect of systemically administered morphine by preventing activation of the putative pain inhibiting output neurons of the RVM, the OFF cells. CCK thus differs from another antiopioid peptide, orphanin FQ/nociceptin, which interferes with opioid analgesia by potently suppressing all OFF-cell firing.


Patients' perspectives of rheumatoid arthritis treatment: a questionnaire survey for the 2020 update of the Japan college of rheumatology clinical practice guidelines.
This study aimed to evaluate patients' opinions regarding their rheumatoid arthritis (RA) therapy and to reflect the patients' perspectives in the 2020 update of the Japan College of Rheumatology clinical practice guidelines. A self-administered questionnaire was mailed to 1600 members of the Japan Rheumatology Friendship Association, who were randomly selected by age and prefecture. A total of 1156 patients returned the questionnaire (response rate, 72.3%; mean age, 63.0 ± 11.9 years). Those who reported having discussed their treatment goals with their doctors (450 respondents, 38.9%) were more likely to be satisfied with their current medical care (odds ratio, 7.13; 95% CI 4.72-10.8) compared with those who had not discussed their goals nor had them explained (287 respondents, 24.8%). The benefits exceeded the adverse effects for all pharmacotherapy (methotrexate, corticosteroids, conventional synthetic antirheumatic drugs, biological agents, Janus kinase inhibitor, and anti-RANKL antibodies). However, while 74.2% of the respondents using biological agents perceived that 'the favorable aspects outweighed the unfavorable aspects,' most of those taking anti-RANKL antibodies (69.2%) felt uncertain. The questionnaire successfully collected information regarding patients' perceptions regarding their therapy. Further implementation of treat-to-target is necessary in Japan to improve patient satisfaction.


In vitro hemodynamic evaluation of ventricular suction conditions of the EVAHEART ventricular assist pump.
Mismatches between pump output and venous return in a continuous-flow ventricular assist device may elicit episodes of ventricular suction. This research describes a series of in vitro experiments to characterize the operating conditions under which the EVAHEART centrifugal blood pump (Sun Medical Technology Research Corp., Nagano, Japan) can be operated with minimal concern regarding left ventricular (LV) suction. The pump was interposed into a pneumatically driven pulsatile mock circulatory system (MCS) in the ventricular apex to aorta configuration. Under varying conditions of preload, afterload, and systolic pressure, the speed of the pump was increased step-wise until suction was observed. Identification of suction was based on pump inlet pressure. In the case of reduced LV systolic pressure, reduced preload (=10 mmHg), and afterload (=60 mmHg), suction was observed for speeds=2,200 rpm. However, suction did not occur at any speed (up to a maximum speed of 2,400 rpm) when preload was kept within 10-14 mmHg and afterload=80 mmHg. Although in vitro experiments cannot replace in vivo models, the results indicated that ventricular suction can be avoided if sufficient preload and afterload are maintained. Conditions of hypovolemia and/or hypotension may increase the risk of suction at the highest speeds, irrespective of the native ventricular systolic pressure. However, in vitro guidelines are not directly transferrable to the clinical situation; therefore, patient-specific evaluation is recommended, which can be aided by ultrasonography at various points in the course of support.


Molecular classification of gastric adenocarcinoma: translating new insights from the cancer genome atlas research network.
Gastric cancer is a heterogenous cancer, which may be classified into several distinct subtypes based on pathology and epidemiology, each with different initiating pathological processes and each possibly having different tumor biology. A classification of gastric cancer should be important to select patients who can benefit from the targeted therapies or to precisely predict prognosis. The Cancer Genome Atlas (TCGA) study collaborated with previous reports regarding subtyping gastric cancer but also proposed a refined classification based on molecular characteristics. The addition of the new molecular classification strategy to a current classical subtyping may be a promising option, particularly stratification by Epstein-Barr virus (EBV) and microsatellite instability (MSI) statuses. According to TCGA study, EBV gastric cancer patients may benefit the programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) antibodies or phosphoinositide 3-kinase (PI3K) inhibitors which are now being developed. The discoveries of predictive biomarkers should improve patient care and individualized medicine in the management since the targeted therapies may have the potential to change the landscape of gastric cancer treatment, moreover leading to both better understanding of the heterogeneity and better outcomes. Patient enrichment by predictive biomarkers for new treatment strategies will be critical to improve clinical outcomes. Additionally, liquid biopsies will be able to enable us to monitor in real-time molecular escape mechanism, resulting in better treatment strategies.


Phosphorylation of ERK in trigeminal spinal nucleus neurons following passive jaw movement in rats with chronic temporomandibular joint inflammation.
To elucidate the neuronal mechanisms underlying chronic pain of the temporomandibular joint (TMJ), expression of phosphorylated extracellular signal-regulated kinase (pERK) in the trigeminal spinal nucleus caudalis (Vc) was studied in rats with a chronically inflamed TMJ. Complete Freund's adjuvant (CFA) was injected in the left TMJ region of rats anesthetized with pentobarbital (50 mg/kg intraperitoneally). Face temperature of the TMJ region was measured periodically after CFA injection. Two weeks after CFA injection, passive jaw movement with 4-, 6-, and 15-mm distances was carried out in inflamed and naive rats for 5, 15, and 30 minutes. pERK expression was studied in the medulla and upper cervical cord after passive jaw movement. Face temperature was significantly increased 2 days after CFA injection and returned to the preoperative level 7 days later. The pERK-like immunoreactive (LI) cells were observed in the dorsal portion of the rostral Vc in inflamed rats after passive jaw movement, and a small number of pERK-LI cells were observed in naive rats after passive jaw movement. No pERK-LI cells were observed in the TMJ of inflamed rats without jaw movement. The number of pERK-LI cells increased following increases in the jaw-movement distance and duration. These findings suggest that the dorsal portion of the rostral Vc may be involved in mediating chronic pain following TMJ inflammation and that the intracellular ERK cascade may be involved.


Impact of aspirin on takotsubo syndrome: a propensity score-based analysis of the InterTAK Registry.
The aim of the present study was to investigate the impact of aspirin on prognosis in takotsubo syndrome (TTS). Patients from the International Takotsubo (InterTAK) Registry were categorized into two groups based on aspirin prescription at discharge. A comparison of clinical outcomes between groups was performed using an adjusted analysis with propensity score (PS) stratification; results from the unadjusted analysis were also reported to note the effect of the PS adjustment. Major adverse cardiac and cerebrovascular events (MACCE: a composite of death, myocardial infarction, TTS recurrence, stroke or transient ischaemic attack) were assessed at 30-day and 5-year follow-up. A total of 1533 TTS patients with known status regarding aspirin prescription at discharge were included. According to the adjusted analysis based on PS stratification, aspirin was not associated with a lower hazard of MACCE at 30-day [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.50-3.04, P = 0.64] or 5-year follow-up (HR 1.11, 95% CI 0.78-1.58, P = 0.58). These results were confirmed by sensitivity analyses performed with alternative PS-based methods, i.e. covariate adjustment and inverse probability of treatment weighting. In the present study, no association was found between aspirin use in TTS patients and a reduced risk of MACCE at 30-day and 5-year follow-up. These findings should be confirmed in adequately powered randomized controlled trials. ClinicalTrials.gov Identifier: NCT01947621.


Serum gamma-glutamyl transferase activity is an independent predictor for cardiovascular disease in obstructive sleep apnea syndrome.
Gamma glutamyl transferase (GGT) is a new marker for predicting myocardial infarction, stroke, cardiac death and inflammation. There is also a strong relationship between Obstructive Sleep Apnea Syndrome (OSAS) and cardiovascular disease. This study was designed to investigate the association between serum GGT levels and cardiovascular disease in patients with OSAS, and relationship between severity of OSAS and serum GGT level. We evaluated the medical records of 166 subjects who were admitted for sleep study. OSAS was diagnosed by polysomnography if Apnea-Hypopnea Index (AHI) > 5. According to AHI, individuals in whom AHI< 5 were recruited as group 1 (OSAS negative group), AHI = 5-15: group 2 (mild OSAS group), AHI = 15-30: group 3 (moderate OSAS group), AHI >30: group 4 (severe OSAS group). Cardiovascular disease was defined if the patients had heart failure, coronary artery disease or arrhythmia. Of the subjects, 112 (67.5%) were male and the mean age was 54.3 ± 12.2 years. There were 22 patients (13.2%), 17 patients (10.2%), 34 patients (20.4%) and 93 patients (56.2%) in group 1, 2, 3 and 4, respectively. There is a significant increase in serum GGT levels while AHI score increases (group 1 = 28.0 ± 10.1, group 2 = 33.8 ± 13.2, group 3 = 35.2 ± 8.5, group 4 = 40.0 ± 22.0; p for trend = 0.024). However, serum C-reactive protein (CRP), alanine aminotransferase and aspartate aminotransferase levels were similar in all groups (p > 0.05). There was a significant independent association between serum GGT levels and the severity of OSAS. Moreover, serum GGT levels were significantly high in patients with cardiovascular disease compared with patients without cardiovascular disease in severe-moderate-mild OSAS (p < 0.05) and OSAS negative groups while CRP levels were not. This was a significant independent association. The present study suggests that high serum GGT level, regardless of the other traditional risk factors, is an independent predictor of cardiovascular disease in patients with OSAS. The results should be confirmed with other randomized prospective studies.


Social participation and health-related quality of life in people with multiple sclerosis.
Social participation is an integral part of everyday life in society; however, evidence about its association with health-related quality of life (HRQoL) in people with multiple sclerosis (MS) is lacking. The aim of this study is to explore whether social participation is associated with the Physical Component Summary of HRQoL (PCS) and Mental Component Summary of HRQoL (MCS) in people with MS, controlled for age, gender, disease severity and disease duration. The sample consisted of 116 consecutive people with MS (response rate: 75.8%; 72.4% women; mean age 40.3 ± 9.8). People with MS completed the Short-Form Health Survey (SF-36) for measuring PCS and MCS and the Participation Scale, which measures the level of social participation. Disability was assessed using the Expanded Disability Status Scale (EDSS). The associations between social participation, PCS and MCS, were analyzed using linear regression that controlled for sociodemographic and clinical variables. PCS was significantly associated with age, disease duration, EDSS and social participation. MCS did not show significant association with the studied variables. Overall, a multiple regression model explained 48% of the PCS variance, while the proportion of MCS variance explained was not significant. Social participation was significantly associated with PCS, suggesting a possibility for intervention in this domain.


Universal patterns or the tale of two systems? Mathematics achievement and educational expectations in post-socialist Europe.
Although communist ideology claimed to destroy former class stratification based on labor market capitalist relationships, de facto during socialism one social class hierarchy was substituted for another that was equally unequal. The economic transition during the 1990s increased stratification by wealth, which affected educational inequality. This study examines the relationships among parental education, gender, educational expectations, and mathematics achievement of youths in five post-socialist Eastern European countries, comparing them with three Western countries. We employed the 8th-grade data from the Trends in International Mathematics and Science Study (TIMSS) 1995 and 2007. The findings point to the universal associations between parental education and student outcomes, whereas gender comparisons present interesting East-West differences. The theoretical and policy implications of these findings are discussed.


GBP5 Repression Suppresses the Metastatic Potential and PD-L1 Expression in Triple-Negative Breast Cancer.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic progression and PD-L1 upregulation in TNBC is still largely unknown. Here, we found that guanylate binding protein 5 (GBP5) is expressed in higher levels in TNBC tissues than in non-TNBC and normal mammary tissues and serves as a poorer prognostic marker in breast cancer patients. Transwell cultivation indicated that GBP5 expression is causally related to cellular migration ability in the detected TNBC cell lines. Moreover, the computational simulation of the gene set enrichment analysis (GSEA) program against the GBP5 signature generated from its coexpression with other somatic genes in TNBC revealed that GBP5 upregulation may be associated with the activation of interferon gamma (IFN-γ)-responsive and NF-κB-related signaling cascades. In addition, we found that the coexpression of GBP5 with PD-L1 was significantly positive correlation in TNBC tissues. Robustly, our data showed that GBP5 knockdown in TNBC cells harboring a higher GBP5 level dramatically suppresses the number of migrated cells, the activity of IFN-γ/STAT1 and TNF-α/NF-κB signaling axes, and the expression of PD-L1. Importantly, the signature combining a higher GBP5 and PD-L1 level predicted the shortest time interval of brain metastasis in breast cancer patients. These findings not only uncover the oncogenic function of GBP5 but also provide a new strategy to combat metastatic/immunosuppressive TNBC by targeting GBP5 activity.


Public health in community pharmacy: a systematic review of pharmacist and consumer views.
The increasing involvement of pharmacists in public health will require changes in the behaviour of both pharmacists and the general public. A great deal of research has shown that attitudes and beliefs are important determinants of behaviour. This review aims to examine the beliefs and attitudes of pharmacists and consumers towards pharmaceutical public health in order to inform how best to support and improve this service. Five electronic databases were searched for articles published in English between 2001 and 2010. Titles and abstracts were screened by one researcher according to the inclusion criteria. Papers were included if they assessed pharmacy staff or consumer attitudes towards pharmaceutical public health. Full papers identified for inclusion were assessed by a second researcher and data were extracted by one researcher. From the 5628 papers identified, 63 studies in 67 papers were included. Pharmacy staff: Most pharmacists viewed public health services as important and part of their role but secondary to medicine related roles. Pharmacists' confidence in providing public health services was on the whole average to low. Time was consistently identified as a barrier to providing public health services. Lack of an adequate counselling space, lack of demand and expectation of a negative reaction from customers were also reported by some pharmacists as barriers. A need for further training was identified in relation to a number of public health services. Consumers: Most pharmacy users had never been offered public health services by their pharmacist and did not expect to be offered. Consumers viewed pharmacists as appropriate providers of public health advice but had mixed views on the pharmacists' ability to do this. Satisfaction was found to be high in those that had experienced pharmaceutical public health There has been little change in customer and pharmacist attitudes since reviews conducted nearly 10 years previously. In order to improve the public health services provided in community pharmacy, training must aim to increase pharmacists' confidence in providing these services. Confident, well trained pharmacists should be able to offer public health service more proactively which is likely to have a positive impact on customer attitudes and health.


A randomised, double-blind trial comparing budesonide formulations and dosages for short-term treatment of eosinophilic oesophagitis.
To investigate the efficacy and safety of two different budesonide formulations (effervescent tablet for orodispersible use (BET) and viscous suspension (BVS)) with different daily dosages for short-term treatment of eosinophilic oesophagitis (EoE). Adults with active EoE (n=76) randomly received 14 days' treatment with either BET 2×1 mg/day (BET1, n=19) or BET 2×2 mg/day (BET2, n=19), or BVS 2×5 mL (0.4 mg/mL)/day (BVS, n=19) or placebo (n=19) in a double-blind, double-dummy fashion, with a 2-week follow-up. Primary end point was histological remission (mean of <16 eosinophils/mm(2 )hpf). Secondary end points included endoscopy score, dysphagia score, drug safety and patient's preference for drug formulation. Histological remission occurred in 100%, 94.7% and 94.7% of budesonide (BET1, BET2, BVS, respectively) and in 0% of placebo recipients (p<0.0001). The improvement in total endoscopic intensity score was significantly higher in the three budesonide groups compared with placebo. Dysphagia improved in all groups at the end of treatment; however, improvement of dysphagia persisted only in those treated with BET1 (p=0.0196 vs placebo). There were no serious adverse events. Local fungal infection (stained fungi) occurred in two patients of each budesonide group (10.5%). The effervescent tablet was preferred by 80% of patients. BET or BVS was highly effective and safe for short-term treatment of EoE. The 1 mg (twice daily) dosage was equally effective as the 2 mg twice daily dosage. The majority of patients preferred the effervescent tablet formulation. NCT02280616; EudraCT number, 2009-016692-29.


Site-specific rectocele repair compared with standard posterior colporrhaphy.
To compare the anatomic and functional outcomes of site-specific rectocele repair and standard posterior colporrhaphy. We reviewed charts of all patients who underwent repair of advanced posterior vaginal prolapse in our institution between July 1998 and June 2002 with at least 1 year of follow-up. This study comprised 124 consecutive patients following site-specific rectocele repair and 183 consecutive patients following standard posterior colporrhaphy without levator ani plication. Baseline characteristics, including age, body mass index, parity, previous pelvic surgeries, and preoperative prolapse were not significantly different between the 2 study groups. Recurrence of rectocele beyond the midvaginal plane (33% versus 14%, P = .001) and beyond the hymenal ring (11% versus 4%, P = .02), recurrence of a symptomatic bulge (11% versus 4%, P = .02), and postoperative Bp point (-2.2 versus -2.7 cm, P = .001) were significantly higher after the site-specific rectocele repair. Rates of postoperative dyspareunia (16% versus 17%), constipation (37% versus 34%), and fecal incontinence (19% versus 18%) were not significantly different between the 2 study groups. Site-specific rectocele repair is associated with higher anatomic recurrence rates and similar rates of dyspareunia and bowel symptoms than standard posterior colporrhaphy. II-3.


Meat, fish, and colorectal cancer risk: the European Prospective Investigation into cancer and nutrition.
Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing. We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend<.001), but was not related to poultry intake. Correcting for measurement error strengthened the associations between colorectal cancer and red and processed meat intake (per 100-g increase HR = 1.25, 95% CI =1.09 to 1.41, Ptrend = .001 and HR = 1.55, 95% CI = 1.19 to 2.02, Ptrend = .001 before and after calibration, respectively) and for fish (per 100 g increase HR = 0.70, 95% CI = 0.57 to 0.87, Ptrend<.001 and HR = 0.46, 95% CI = 0.27 to 0.77, Ptrend = .003; before and after correction, respectively). In this study population, the absolute risk of development of colorectal cancer within 10 years for a study subject aged 50 years was 1.71% for the highest category of red and processed meat intake and 1.28% for the lowest category of intake and was 1.86% for subjects in the lowest category of fish intake and 1.28% for subjects in the highest category of fish intake. Our data confirm that colorectal cancer risk is positively associated with high consumption of red and processed meat and support an inverse association with fish intake.


Methane production, nutrient digestion, ruminal fermentation, N balance, and milk production of cows fed timothy silage- or alfalfa silage-based diets.
The objective of this study was to investigate the effects of changing forage source in dairy cow diets from timothy silage (TS) to alfalfa silage (AS) on enteric CH₄ emissions, ruminal fermentation characteristics, digestion, milk production, and N balance. Nine ruminally cannulated lactating cows were used in a replicated 3 × 3 Latin square design (32-d period) and fed (ad libitum) a total mixed ration (TMR; forage:concentrate ratio of 60:40, dry matter basis), with the forage portion consisting of either TS (0% AS; 0% AS and 54.4% TS in the TMR), a 50:50 mixture of both silages (50% AS; 27.2% AS and 27.2% TS in the TMR), or AS (100% AS; 54.4% AS and 0% TS in the TMR). Compared with TS, AS contained less (36.9 vs. 52.1%) neutral detergent fiber but more (20.5 vs. 13.6%) crude protein (CP). In sacco 24-h ruminal degradability of organic matter (OM) was higher for AS than for TS (73.5 vs. 66.9%). Replacement of TS with AS in the diet entailed increasing proportions of corn grain and bypass protein supplement at the expense of soybean meal. As the dietary proportion of AS increased, CP and starch concentrations increased, whereas fiber content declined in the TMR. Dry matter intake increased linearly with increasing AS proportions in the diet. Apparent total-tract digestibility of OM and gross energy remained unaffected, whereas CP digestibility increased linearly and that of fiber decreased linearly with increasing inclusion of AS in the diet. The acetate-to-propionate ratio was not affected, whereas ruminal concentration of ammonia (NH₃) and molar proportion of branched-chain VFA increased as the proportion of AS in the diet increased. Daily CH₄ emissions tended to increase (476, 483, and 491 g/d for cows fed 0% AS, 50% AS, and 100% AS, respectively) linearly as cows were fed increasing proportions of AS. Methane production adjusted for dry matter intake (average=19.8 g/kg) or gross energy intake (average=5.83%) was not affected by increasing AS inclusion in the diet. When expressed on a fat-corrected milk or energy-corrected milk yield basis, CH₄ production increased linearly with increasing AS dietary proportion. Urinary N excretion (g/d) increased linearly when cows were fed increasing amounts of AS in the diet, suggesting a potential for higher nitrous oxide (N₂O) and NH₃ emissions. Efficiency of dietary N use for milk protein secretion (g of milk N/g of N intake) declined with the inclusion of AS in the diet. Despite marked differences in chemical composition and ruminal degradability, under the conditions of this study, replacing TS with AS in dairy cow diets was not effective in reducing CH₄ energy losses.


Ethnicity, pre-existing comorbidities, and outcomes of hospitalised patients with COVID-19.
Background: The coronavirus disease 2019 (COVID-19) pandemic has resulted in thousands of deaths in the UK. Those with existing comorbidities and minority ethnic groups have been found to be at increased risk of mortality. We wished to determine if there were any differences in intensive care unit (ICU) admission and 30-day hospital mortality in a city with high levels of deprivation and a large community of people of South Asian heritage. Methods: Detailed information on 582 COVID-19-positive inpatients in Bradford and Calderdale between February-August 2020 were extracted from Electronic Health Records. Logistic regression and Cox proportional hazards models were used to explore the relationship between ethnicity with admission to ICU and 30-day mortality, respectively accounting for the effect of demographic and clinical confounders. Results: The sample consisted of 408 (70%) White, 142 (24%) South Asian and 32 (6%) other minority ethnic patients. Ethnic minority patients were younger, more likely to live in deprived areas, and be overweight/obese, have type 2 diabetes, hypertension and asthma compared to white patients, but were less likely to have cancer (South Asian patients only) and COPD. Male and obese patients were more likely to be admitted to ICU, and patients of South Asian ethnicity, older age, and those with cancer were less likely. Being male, older age, deprivation, obesity, and cancer were associated with 30-day mortality. The risk of death in South Asian patients was the same as in white patients HR 1.03 (0.58, 1.82). Conclusions: Despite South Asian patients being less likely to be admitted to ICU and having a higher prevalence of diabetes and obesity, there was no difference in the risk of death compared to white patients. This contrasts with other findings and highlights the value of studies of communities which may have different ethnic, deprivation and clinical risk profiles.


Steroidal and nonsteroidal sulfamates as potent inhibitors of steroid sulfatase.
Synthetic routes to potent steroidal and nonsteroidal sulfamate-based active site-directed inhibitors of the enzyme steroid sulfatase, a topical target in the treatment of postmenopausal women with hormone-dependent breast cancer, are described. Novel compounds were examined for estrone sulfatase (E1-STS) inhibition in intact MCF-7 breast cancer cells and placental microsomes. Reaction of the sodium salt of estrone with sulfamoyl chloride gave estrone 3-O-sulfamate (EMATE, 2) which inhibits E1-STS activity potently (> 99% at 0.1 microM in intact MCF-7 cells, IC50 = 65 pM) in a time- and concentration-dependent manner, suggesting that EMATE is an active site-directed inhibitor. EMATE is also active in vivo orally. 5,6,7,8-Tetrahydronaphthalene 2-O-sulfamate (7) and its N-methylated derivatives (8 and 9) were synthesized, and 7 inhibits the E1-STS activity in intact MCF-7 cells by 79% at 10 microM. 4-Methylcoumarin 7-O-sulfamate (COUMATE) and its derivatives (14, 16, and 18) were prepared to extend this series of nonsteroidal inhibitors, and COUMATE reduces the E1-STS activity in placental microsomes by > 90% at 10 microM. Although the orally active COUMATE is less potent than EMATE as an active site-directed inhibitor, it has the important advantage of being nonestrogenic. Analogues (20, 22, 24, 26, 27, 31, 33, 39, and 44) of COUMATE were synthesized to study its structure-activity relationships, and sulfamates of tetralones (46 and 48) and indanones (49, 51, and 53) were also prepared. While most of these compounds were found to inhibit E1-STS activity less effectively than COUMATE, one analogue, 3,4-dimethylcoumarin 3-O-sulfamate (24), was found to be some 12-fold more potent than COUMATE as an E1-STS inhibitor in intact MCF-7 cells (IC50 = 30 nM for 24, cf. 380 nM for COUMATE). Hence, highly potent sulfamate-based inhibitors of steroid sulfatase, such as EMATE, COUMATE, and 24, possess therapeutic potential and will allow the importance of estrogen formation in breast tumors via the E1-STS pathway to be assessed. A pharmacophore for active site-directed sulfatase inhibition is proposed.


Contributions of Asn2198, Met2199, and Phe2200 in the factor VIII C2 domain to cofactor activity, phospholipid-binding, and von Willebrand factor-binding.
The crystal structure of the factor VIII C2 domain consists of a beta-sandwich core from which beta-hairpins and loops extend to form a hydrophobic surface. The hydrophobic surface includes M2199 and F2200 at the tip of the 1(st) beta-hairpin. To determine the individual contributions of residues N2198, M2199, and F2200 to phospholipid and von Willebrand factor (vWF) binding properties of factor VIII, we prepared mutant proteins with single alanine substitutions. We found that single mutations at N2198 and M2199 had relatively little impact on cofactor activity, or phospholipid and vWF binding. However the F2200A mutant had slightly lower cofactor activity at subsaturating phospholipid concentrations. Competitive ELISAs suggested that F2200 plays a more important role in both phospholipid-binding and vWF-binding than N2198 and M2199. All mutant proteins were still recognized by a monoclonal antibody and two factor VIII inhibitors that neutralized cofactor activity and blocked factor VIII binding to phospholipids.


Anterior decompression and fusion via the extrapleural approach for thoracic disc herniation causing myelopathy.
Anterior decompression and fusion via an extrapleural approach was performed for 33 patients with myelopathy arising from thoracic disc herniation and the clinical usefulness and problems related to this procedure were assessed on the basis of surgical results and complications. The severity of the myelopathy was evaluated by the Japanese Orthopaedic Association score, and the surgical results were based on the recovery rate. The upper-level limit of decompression and fusion via the extrapleural approach was T4-5. The recovery rate for the mean postoperative follow-up period of 41 months was 66.7%. An age of 60 years or more, long duration of illness and severe preoperative myelopathy were indicators of a poor prognosis. Two patients suffered from a postoperative transient pulmonary complication due to hemothorax. X-ray examinations revealed good bone union in all the patients. The present study indicates that anterior decompression and fusion via the extrapleural approach is a useful technique which can be used to achieve a high success rate in the surgical treatment of thoracic disc herniation, if intervention is early.


Fundamentals of randomized clinical trials in wound care: reporting standards.
In wound care research, available high-level evidence according to the evidence pyramid is rare, and is threatened by a poor study design and reporting. Without comprehensive and transparent reporting, readers will not be able to assess the strengths and limitations of the research performed. Randomized clinical trials (RCTs) are universally acknowledged as the study design of choice for comparing treatment effects. To give high-level evidence the appreciation it deserves in wound care, we propose a step-by-step reporting standard for comprehensive and transparent reporting of RCTs in wound care. Critical reporting issues (e.g., wound care terminology, blinding, predefined outcome measures, and a priori sample size calculation) and wound-specific barriers (e.g., large diversity of etiologies and comorbidities of patients with wounds) that may prevent uniform implementation of reporting standards in wound care research are addressed in this article. The proposed reporting standards can be used as guidance for authors who write their RCT, as well as for peer reviewers of journals. Endorsement and application of these reporting standards may help achieve a higher standard of evidence and allow meta-analysis of reported wound care data. The ultimate goal is to help wound care professionals make better decisions for their patients in clinical practice.


Crystal structures and biochemical characterization of DNA sliding clamps from three Gram-negative bacterial pathogens.
Bacterial sliding clamps bind to DNA and act as protein-protein interaction hubs for several proteins involved in DNA replication and repair. The partner proteins all bind to a common pocket on sliding clamps via conserved linear peptide sequence motifs, which suggest the pocket as an attractive target for development of new antibiotics. Herein we report the X-ray crystal structures and biochemical characterization of β sliding clamps from the Gram-negative pathogens Pseudomonas aeruginosa, Acinetobacter baumannii and Enterobacter cloacae. The structures reveal close similarity between the pathogen and Escherichia coli clamps and similar patterns of binding to linear clamp-binding motif peptides. The results suggest that linear motif-sliding clamp interactions are well conserved and an antibiotic targeting the sliding clamp should have broad-spectrum activity against Gram-negative pathogens.


The short isoform of the host antiviral protein ZAP acts as an inhibitor of SARS-CoV-2 programmed ribosomal frameshifting.
Programmed ribosomal frameshifting (PRF) is a fundamental gene expression event in many viruses, including SARS-CoV-2. It allows production of essential viral, structural and replicative enzymes that are encoded in an alternative reading frame. Despite the importance of PRF for the viral life cycle, it is still largely unknown how and to what extent cellular factors alter mechanical properties of frameshift elements and thereby impact virulence. This prompted us to comprehensively dissect the interplay between the SARS-CoV-2 frameshift element and the host proteome. We reveal that the short isoform of the zinc-finger antiviral protein (ZAP-S) is a direct regulator of PRF in SARS-CoV-2 infected cells. ZAP-S overexpression strongly impairs frameshifting and inhibits viral replication. Using in vitro ensemble and single-molecule techniques, we further demonstrate that ZAP-S directly interacts with the SARS-CoV-2 RNA and interferes with the folding of the frameshift RNA element. Together, these data identify ZAP-S as a host-encoded inhibitor of SARS-CoV-2 frameshifting and expand our understanding of RNA-based gene regulation.


Predicting drug-induced QT prolongation effects using multi-view learning.
Drug-induced QT prolongation is a major life-threatening adverse drug effect. It is crucial to predict the QT prolongation effect as early as possible in drug development, however, data on drugs that induce QT prolongation are very limited and noisy. Multi-view learning (MVL) has been applied to many challenging machine learning and data mining problems, especially when complex data from diverse domains are involved and only limited labeled examples are available. Unlike existing MVL methods that use l2-norm co-regularization to obtain a smooth objective function, in this paper we proposed an l1-norm co-regularized MVL algorithm for predicting drug-induced QT prolongation effect and reformulate the l1-norm co-regularized objective function for deriving its gradient in the analytic form, and we can optimize the mapping functions on all views simultaneously and achieve 3-4 times higher computational efficiency, while previous l2-norm co-regularized MVL methods use alternate optimization that alternately optimizes one view with the other views fixed until convergence. l1 -norm co-regularization enforces sparsity in the learned mapping functions and hence the results are expected to be more interpretable. Comprehensive experimental comparisons between our proposed method and previous MVL and single-view learning methods demonstrate that our method significantly outperforms those baseline methods more efficiently.


Repetitive Transcranial Magnetic Stimulation for the Treatment of Executive Function Deficits in Autism Spectrum Disorder: Clinical Trial Approach.
Executive function (EF) deficits in patients with autism spectrum disorder (ASD) are ubiquitous and understudied. Further, there are no effective, neuroscience-based treatments to address this impairing feature of ASD. Repetitive transcranial magnetic stimulation (rTMS) has demonstrated promise in addressing EF deficits in adult neuropsychiatric disorders. This article will outline the design of a novel randomized-controlled trial of bilateral, 20 Hz, rTMS applied to the dorsolateral prefrontal cortex (DLPFC) for treatment of EF deficits in ASD that is currently ongoing. We describe prior therapeutic rTMS research for ASD and prior rTMS trials targeting EFs in adult neuropsychiatric disorders. A neurophysiological rationale for rTMS treatment of EF deficits in ASD is presented. An ongoing protocol will enroll participants aged 16-35 with ASD and no intellectual disability. Psychotropic medications will be continued during the 4-week trial of active 20 Hz versus sham rTMS applied to the DLPFC. Twenty, active treatment sessions consisting of 25 stimulation trains at a 90% motor threshold will be administered. The primary outcome measure is the Cambridge Neuropsychological Test Automated Battery (CANTAB) spatial working memory task. At present, recruitment, enrollment, and treatment within the described clinical trial are ongoing. EF deficits are common and impairing symptoms of ASD. There are no evidence-based treatments for EF deficits in ASD. The protocol described here will provide important preliminary data on the feasibility and efficacy of 20 Hz rTMS to DLPFC for EF deficits in ASD.


In vivo and ex vivo analysis of tubule function.
Analysis of tubule function with in vivo and ex vivo approaches has been instrumental in revealing renal physiology. This work allows assignment of functional significance to known gene products expressed along the nephron, primary of which are proteins involved in electrolyte transport and regulation of these transporters. Not only we have learned much about the key roles played by these transport proteins and their proper regulation in normal physiology but also the combination of contemporary molecular biology and molecular genetics with in vivo and ex vivo analysis opened a new era of discovery informative about the root causes of many renal diseases. The power of in vivo and ex vivo analysis of tubule function is that it preserves the native setting and control of the tubule and proteins within tubule cells enabling them to be investigated in a "real-life" environment with a high degree of precision. In vivo and ex vivo analysis of tubule function continues to provide a powerful experimental outlet for testing, evaluating, and understanding physiology in the context of the novel information provided by sequencing of the human genome and contemporary genetic screening. These tools will continue to be a mainstay in renal laboratories as this discovery process continues and as we continue to identify new gene products functionally compromised in renal disease.


VirtualPlant: a software platform to support systems biology research.
Data generation is no longer the limiting factor in advancing biological research. In addition, data integration, analysis, and interpretation have become key bottlenecks and challenges that biologists conducting genomic research face daily. To enable biologists to derive testable hypotheses from the increasing amount of genomic data, we have developed the VirtualPlant software platform. VirtualPlant enables scientists to visualize, integrate, and analyze genomic data from a systems biology perspective. VirtualPlant integrates genome-wide data concerning the known and predicted relationships among genes, proteins, and molecules, as well as genome-scale experimental measurements. VirtualPlant also provides visualization techniques that render multivariate information in visual formats that facilitate the extraction of biological concepts. Importantly, VirtualPlant helps biologists who are not trained in computer science to mine lists of genes, microarray experiments, and gene networks to address questions in plant biology, such as: What are the molecular mechanisms by which internal or external perturbations affect processes controlling growth and development? We illustrate the use of VirtualPlant with three case studies, ranging from querying a gene of interest to the identification of gene networks and regulatory hubs that control seed development. Whereas the VirtualPlant software was developed to mine Arabidopsis (Arabidopsis thaliana) genomic data, its data structures, algorithms, and visualization tools are designed in a species-independent way. VirtualPlant is freely available at www.virtualplant.org.


TSLP promotes interleukin-3-independent basophil haematopoiesis and type 2 inflammation.
CD4(+) T-helper type 2 (T(H)2) cells, characterized by their expression of interleukin (IL)-4, IL-5, IL-9 and IL-13, are required for immunity to helminth parasites and promote the pathological inflammation associated with asthma and allergic diseases. Polymorphisms in the gene encoding the cytokine thymic stromal lymphopoietin (TSLP) are associated with the development of multiple allergic disorders in humans, indicating that TSLP is a critical regulator of T(H)2 cytokine-associated inflammatory diseases. In support of genetic analyses, exaggerated TSLP production is associated with asthma, atopic dermatitis and food allergies in patients, and studies in murine systems demonstrated that TSLP promotes T(H)2 cytokine-mediated immunity and inflammation. However, the mechanisms through which TSLP induces T(H)2 cytokine responses remain poorly defined. Here we demonstrate that TSLP promotes systemic basophilia, that disruption of TSLP-TSLPR interactions results in defective basophil responses, and that TSLPR-sufficient basophils can restore T(H)2-cell-dependent immunity in vivo. TSLP acted directly on bone-marrow-resident progenitors to promote basophil responses selectively. Critically, TSLP could elicit basophil responses in both IL-3-IL-3R-sufficient and -deficient environments, and genome-wide transcriptional profiling and functional analyses identified heterogeneity between TSLP-elicited versus IL-3-elicited basophils. Furthermore, activated human basophils expressed TSLPR, and basophils isolated from eosinophilic oesophagitis patients were distinct from classical basophils. Collectively, these studies identify previously unrecognized heterogeneity within the basophil cell lineage and indicate that expression of TSLP may influence susceptibility to multiple allergic diseases by regulating basophil haematopoiesis and eliciting a population of functionally distinct basophils that promote T(H)2 cytokine-mediated inflammation.


I-region genes are expressed on T and B lymphocytes. Studies of the mixed lymphocyte reaction (MLR).
Unidirectional mixed lymphocyte reactions (MLR) were performed between mouse strains differing for various segments within the H-2 complex. Thymocytes and purified lymph node T cells and B cells were used as stimulator cells. In three of five combinations studied, differing only within the I region, both T and B cells stimulated in the MLR. This suggests that the region codes for both T- and B-cell surface structures. However, if the difference was restricted to one I subregion (I-C), only T cells stimulated. This finding suggests that some of the I-region genes may be expressed either in T or in B cells.


Coordination of T cell activation and migration through formation of the immunological synapse.
T cell activation is based on interactions of T cell antigen receptors with MHC-peptide complexes in a specialized cell-cell junction between the T cell and antigen-presenting cell-the immunological synapse. The immunological synapse coordinates naïve T cell activation and migration by stopping T cell migration with antigen-presenting cells bearing appropriate major histocompatibility complex (MHC) peptide complexes. At the same time, the immunological synapse allows full T cell activation through sustained signaling over a period of several hours. The immunological synapse supports activation in the absence of continued T cell migration, which is required for T cell activation through serial encounters. Src and Syk family kinases are activated early in immunological synapse formation, but this signaling process returns to the basal level after 30 min; at the same time, the interactions between T cell receptors (TCRs) and MHC peptides are stabilized within the immunological synapse. The molecular pattern of the mature synapse in helper T cells is a self-stabilized structure that is correlated with cytokine production and proliferation. I propose that this molecular pattern and its specific biochemical constituents are necessary to amplify signals from the partially desensitized TCR.


Postural set for balance control is normal in Alzheimer's but not in Parkinson's disease.
It has been suggested that patients with dementia of the Alzheimer type have abnormalities in the basal ganglia, and thus, may have similar sensorimotor problems as patients with basal ganglia degeneration from Parkinson's disease. Whether the similarity extends to balance control is unknown. One distinguishing feature of balance disorder in Parkinson's disease is difficulty with changing postural set in terms of adapting the amplitude of leg muscle activity as a function of support condition. We, therefore, tested whether patients with Alzheimer's disease without extrapyramidal signs would show a similar problem in changing postural set as patients with Parkinson's disease. The ability to quickly change postural set was measured by comparing leg muscle activity under two conditions of support (free stance, versus grasping a frame, or sitting) during backward surface translations, during toes up surface rotations, and during voluntary rise to toes. Results were compared among 12 healthy adults, 8 nondemented Parkinson's patients on their usual dose of medication, and 11 Alzheimer patients without extrapyramidal signs. Subjects with Alzheimer's, but not Parkinson's, disease performed similarly to the healthy control subjects. They changed postural set immediately, by suppressing leg muscle activity to low levels when supported. Parkinson subjects did not change postural set immediately. They did not suppress the tibialis anterior in voluntary rise to toes when holding, nor the soleus in perturbed sitting as much as the healthy control and Alzheimer subjects in the first trial. Instead, the Parkinson subjects changed set more slowly, over repeated and consecutive trials in both protocols. The onset latencies of soleus responses to backward surface translations and perturbed sitting, as well as tibialis anterior responses to toes up rotations, were the same for all three groups. Alzheimer patients without extrapyramidal signs, unlike nondemented Parkinson's disease patients, have no difficulty in quickly changing postural set in response to altered support conditions. Our results, therefore, do not support the hypothesis that Parkinson's and uncomplicated Alzheimer's diseases share common postural set problems that may contribute to disordered balance control.


Comparative study of alendronate versus etidronate for the treatment of Paget's disease of bone.
Alendronate, an aminobisphosphonate, is much more potent than etidronate, an older bisphosphonate, in inhibiting osteoclast-mediated bone resorption, and unlike etidronate, therapeutic doses of alendronate are not associated with abnormal mineralization. In the present study, we compared the effectiveness, safety, and tolerability of 6 months of daily oral administration of alendronate (40 mg) with those of etidronate (400 mg) in 89 patients with clinically active Paget's disease. The primary efficacy end point was the percent change in serum alkaline phosphatase. Other end points included changes in urinary deoxypyridinoline excretion, pain, functional impairment scores, and radiological osteolysis. Tetracycline-labeled bone biopsies were obtained for histomorphometric analysis from a subset of 43 patients at the 6-month visit. The alendronate-treated group had significantly greater decreases in both serum alkaline phosphatase (79% vs. 44%) and urinary deoxypyridinoline (75% vs. 51%) than the etidronate-treated group (P < 0.001 in both cases). Normalization of serum alkaline phosphatase was much more frequent in alendronate-treated patients (63.4% vs. 17.0%; P < 0.001). Alendronate was well tolerated and had a safety profile similar to that of etidronate. Histomorphometry revealed decreased bone turnover and no qualitative abnormalities, including no direct negative effects on bone mineralization, with alendronate treatment. One patient receiving etidronate developed frank osteomalacia. Alendronate appears to be a highly effective treatment for Paget's disease of bone that offers an important therapeutic advance over etidronate.


Steady-state chemotaxis in Escherichia coli.
The bacterium E. coli maneuvers itself to regions with high chemoattractant concentrations by performing two stereotypical moves: "runs," in which it moves in near-straight lines, and "tumbles," in which it does not advance but changes direction randomly. The duration of each move is stochastic and depends upon the chemoattractant concentration experienced in the recent past. We relate this stochastic behavior to the steady-state density of a bacterium population, and we derive the latter as a function of chemoattractant concentration. In contrast to earlier treatments, here we account for the effects of temporal correlations and variable tumbling durations. A range of behaviors is obtained that depends subtly upon several aspects of the system -- memory, correlation, and tumbling stochasticity, in particular.


Single-pair FRET characterization of DNA tweezers.
The self-assembly properties of DNA make it an ideal choice for the construction of nanomachines such as DNA tweezers. Because nanomachines function as individual units, they need to be studied on the single-molecule level. From single-pair FRET investigations, we show that "open" tweezers exist in a single conformation with minimal FRET efficiency, whereas upon addition of a "closing strand", three conformations are observed, which are averaged out in ensemble measurements.